Eleven of 12 nonvaccinated volunteers developed malaria infections after controlled exposure to infected mosquitoes in the trial, the researchers said online in Science.

"Demonstration of high-level protection by IV administration is a critical first step in the development of the PfSPZ [P. falciparum sporozoite] vaccine," they wrote.

"Future studies will determine the duration of protection and degree of protection against heterologous strains of Pf, establish immune correlates of protection, and optimize approaches to deliver IV vaccine administration to achieve the coverage in mass administration campaigns needed to eliminate Pf malaria from defined areas," they added.

Malaria is one of the most important infectious diseases worldwide, killing approximately a million people annually in tropical areas. Although current drugs are fairly effective, they are not affordable everywhere and resistance is a growing problem.

Seder and colleagues noted that immunity to malaria is known to be possible, but the only really successful approach before now was to have people bitten by a thousand or more Plasmodium-infected, irradiated mosquitoes. That was accomplished 40 years ago.

Attempts to develop an effective vaccine based on attenuated Plasmodium organisms that could be delivered by intradermal or subcutaneous injection failed, leading Seder and colleagues to try intravenous delivery.

In the current study, a total of 57 individuals were recruited, 40 of whom received the investigational vaccine at doses of 7,500, 30,000, or 135,000 radiation-attenuated sporozoites per infusion.

From four to six infusions were given, at 4-week intervals except in two individuals receiving six infusions of the lowest dosage, who had an 8-week interval between the second and third doses. Also, the protocol was changed for individuals assigned to receive six infusions of the highest doses such that they only received five, and the fifth dose came 7 weeks after the fourth.

Four participants did not receive all the scheduled doses and were excluded from the efficacy analyses. Two were studied for safety only and did not undergo the malaria challenge.

The challenge consisted of five bites from malaria-infected mosquitoes about 3 weeks after the final vaccine dose. Blood samples were taken daily to assess parasitemia. "Subjects were considered protected if [blood] smears were negative through day 28" after the challenge, Seder and colleagues explained. Twelve unvaccinated volunteers underwent the challenge as well, 11 of them developing parasitemia.

Participants receiving the 7,500-sporozoite doses all developed parasitemia and as quickly as the unvaccinated controls, the researchers indicated.

Of nine who received four doses of the 30,000-sporozoite preparation, eight developed parasitemia but with a delay of 1.4 days relative to controls (P=0.007), suggesting "a modest reduction in the numbers of liver stage parasites," Seder and colleagues wrote. The ninth participant did not develop parasitemia.

The high-strength, 135,000-sporozoite version was given to nine participants in four doses and to six participants in five doses. All of those receiving five doses were parasite-negative through day 28, as were six of those given four doses.

Seder and colleagues indicated that this level of protection far exceeded that seen with previous malaria vaccines, except for the old study involving irradiated mosquitoes. One of the most promising candidates showed initial efficacy of about 50% in preventing infection, which waned to less than 20% in 4 years.

Adverse events included transient, asymptomatic elevations in liver enzymes in 40% of vaccinated participants, "assessed as possibly related to vaccination," according to Seder and colleagues. No dose relationship was seen with these events. Two participants had serious adverse events: colon cancer in one participant and headache and anxiety in another following treatment with chloroquine in the trial's challenge phase. The investigators determined that these latter effects were chloroquine side effects, which resolved within 1 month.

The study was supported by Sanaria, which developed the vaccine candidate, the NIH, the Naval Medical Research Center, and the Walter Reed Army Institute of Research.

Several co-authors were Sanaria employees. No other potential conflicts of interest were reported.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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